Fig. 1

Outward- versus inward-looking genes. A Summary description of the characteristcs of inward-looking and outward-looking gene families and their genomic distinctions. This table is inspired by Holmquist [57]. Descriptions derive from our analyses here and from references cited throughout the text. B Model of possible relationships between expansion of gene families in cis, genomic architecture, selective forces, and mode of expression. We hypothesize that as gene families duplicate in cis, selection on the amino acid sequence of individual family members weakens, while selection against recombination strengthens. Together, these effects would result in loss of GC bases over evolutionary time. Once a tandem array is AT-rich, it is more likely to be heterochromatinized and acquires highly tissue-specific expression patterns. The “quarantining” of expression reduces the phenotypic consequences of change in copy number, allowing further rounds of gene gain; nevertheless, the numbers of intact genes in certain families correlates with natural history and is likely under selection [58,59,60,61]. This mode of “birth-and-death evolution” also results in frequent gene loss through pseudogenization [17, 18, 62]. We expect that while forces described here are important contributors to emergence of sequence bias, our model is incomplete—there are likely to be additional neutral or selective mechanisms that make important contributions to the emergence of sequence bias in outward-looking tandem arrays. These could include the basal sequence content of a gene prior to any duplication, sequence effects of the molecular mechanism that produces gene duplication, differential amino acid usage in different kinds of proteins, or selective mechanisms that preferentially retain duplicates with weak promoters. Ultimately, these forces result in the observed gene content in mammalian isochores, where outward-looked arrays (reds and browns) are enriched in AT-rich regions, and single-copy genes with inward-looking functions (other colors) in GC-rich isochores